Higher insulin resistance in African Americans has been suggested to disproportionately predispose this population to a host of cardio-metabolic disorders including obesity, type 2 diabetes and cardiovascular disease. We seek to transform this epidemiologic finding into the hypothesis that the inverse relationship between insulin resistance and the adipocyte-specific hormone, adiponectin, can be the basis for a novel treatment paradigm in cardio-metabolic disorders. A significant body of literature confirms the insulin-sensitizing, anti-inflammatory and cardioprotective properties of adiponectin. There is also substantial evidence of ethnic variation in adiponectin levels. More specifically, adiponectin levels are lower in African Americans and could partly explain the higher insulin resistance and attendant cardio-metabolic disease risk in this population. Polymorphisms in the adiponectin gene have been associated with adiponectin levels and insulin-sensitivity in Caucasian and Asian populations; however, there is a critical lack of comparable polymorphism mapping of adiponectin in African Americans. Also, despite the accumulation of certain mechanistic insights into adiponectin function, the full spectrum of adiponectin biology is yet to be elucidated through systems biology approaches. Finally, suitable in vitro assays for evaluating candidate adiponectin regulators identified from genetic and systems biology approaches are also lacking. To address these gaps, we propose translational research at the cellular, animal and population levels to critically evaluate adiponectin as a biologic mediator of, and a possible therapeutic target for, cardio-metabolic risk reduction. The unifying objective behind the proposed study is expansion of our understanding of adiponectin biology with reference to health disparities and development of key resources for enabling future investigations into adiponectin-modifying treatments. Since hypoadiponectinemia is frequently observed in African-Americans, our research carries added significance for addressing health disparities in minority populations.